1. Field of the Invention
The present invention is generally related to a process for the preparation of cyclophosphamide, and more particularly to a solvent-free process for the preparation of cyclophosphamide.
2. Description of the Prior Art
In recent years, it is well known that cyclophosphamide and its derivatives have cytostatic and immunosuppressant's activity. Cyclophosphamide presents a high potent character as an anti-cancer/anti-tumor drug. During the preparation of cyclophosphamide, it is essential to have high purity of the product and also the conversion yield of the synthesis.
In literature, all the procedures of preparing cyclophosphamide required an inert organic solvent or solvent mixtures. The solvent(s) used are not parts of constitution of the molecule and it will increase the total volume of the reaction for preparing cyclophosphamide which will decrease the volume efficiency. Cyclophosphamide is a high potency drug, and it has high bioactivity in human body with a very small dosage. Therefore, it is very important to protect the operator(s) during the manufacturing of high potency drug and controls the environment of production facilities. Generally speaking, high potency drug such as cyclophosphamide is produced with small volume reaction reactors due to the control and safety concerns. When the used solvent occupies most volume of the reaction tanks, the manufacturing efficiency will be decreased and the batch efficiency for the preparation of cyclophosphamide will decrease. The manufacturing cost will increase as the result of poor throughputs. And it is also true that the solvents used in the reaction will let the operator(s) expose in volatile organic solvent(s) which may contain trace amount of cyclophosphamide because of its low vapor pressure property of cyclophosphamide. This will present a hazard-working environment for the operators.
It is well disclosed in literature that it is important to control the amount of water in the reaction mixture for the preparation of cyclophosphamide. While the amount of water is increased during preparing cyclophosphamide, the amount of by-product(s) will be increased and the total conversion yield will be decreased. The solvents used in the reaction are the major source of the water that needed be controlled. When large amount of solvents are used, it absolutely need to decrease the water content of solvent by either distillation under anhydrous conditions before use or by other means such as using dehydrate reagents during the reaction. Molecular sieves and CaCl2 are commonly added into the reaction mixture to remove water as part of the preparing procedures.
In the prior literature, dichloromethane or dioxane can be used as solvent for preparing cyclophosphamide. It is well known that the water contained in dioxane is hard to be removed and the by-products will increase as the results of high water contents in the reaction. Dioxane is a toxic solvent and it is not only dangerous to the operator(s) but also bring an added-cost to prevent pollution after the reaction.
From the discussion as stated, to develop a novel solvent-free process for the preparation of cyclophosphamide is important. It offers the advantages of high conversion rate, high throughputs and easy environmental and operation control with great cost benefits.